Rapid onset of efficacy predicts response to therapy with certolizumab plus methotrexate in patients with active rheumatoid arthritis

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1 ORIGINAL ARTICLE Korean J Intern Me 218;33: Rapi onset of effiay preits response to therapy with ertolizumab plus methotrexate in patients with ative rheumatoi arthritis Young Mo Kang 1, Young-Eun Park 2, Won Park 3, Jung-Yoon Choe 4, Chul-Soo Cho 5, Seung-Cheol Shim 6, Sang Cheol Bae 7, Chang-Hee Suh 8, Hoon-Suk Cha 9, Eun Mi Koh 9, Yeong-Wook Song 1, Bin Yoo 11, Shin-Seok Lee 12, Min-Chan Park 13, Sang-Heon Lee 14, Catherine Arent 15, Willem Koetse 16, an Soo-Kon Lee 17 1 Division of Rheumatology, Department of Internal Meiine, Shool of Meiine, Kyungpook National University, Daegu; 2 Division of Rheumatology, Department of Internal Meiine, Pusan National University Hospital, Busan; 3 Division of Rheumatology, Department of Internal Meiine, Inha University Hospital, Inheon; 4 Department of Internal Meiine, Daegu Catholi University Meial Center, Daegu; 5 Division of Rheumatology, Department of Internal Meiine, College of Meiine, Seoul St. Mary's Hospital, The Catholi University of Korea, Seoul; 6 Division of Rheumatology, Department of Internal Meiine, Chungnam National University Hospital, Daejeon; 7 Department of Rheumatology, Hanyang University Hospital for Rheumati Diseases, Seoul; 8 Division of Rheumatology, Department of Internal Meiine, Ajou University Hospital, Suwon; 9 Division of Rheumatology, Department of Internal Meiine, Sungkyunkwan University Shool of Meiine, Suwon; 1 Division of Rheumatology, Department of Internal Meiine, Seoul National University Hospital, Seoul; 11 Division of Rheumatology, Department of Internal Meiine, Asan Meial Center, University of Ulsan College of Meiine, Seoul; 12 Division of Rheumatology, Department of Internal Meiine, Chonnam National University Hospital, Gwangju; 13 Division of Rheumatology, Department of Internal Meiine, Gangnam Severane Hospital, Yonsei University College of Meiine, Seoul; 14 Division of Rheumatology, Department of Internal Meiine, Konkuk University Meial Center, Seoul, Korea; 15 UCB Pharma, Brainel Alleu, Belgium; 16 UCB Pharma, Raleigh, NC, USA; 17 Division of Rheumatology, Department of Internal Meiine, Severane Hospital, Yonsei University College of Meiine, Seoul, Korea Bakgroun/Aims: The objetive of this stuy was to etermine the effiay an safety of a-on therapy with ertolizumab pegol (CZP) in ative rheumatoi arthritis (RA) patients of a single ethniity. Methos: In this 24-week, phase 3, ranomize, ouble-blin, plaebo-ontrolle trial, eligible patients (n = 127) were ranomize 2:1 to subutaneous CZP + methotrexate (MTX; 4 mg at week, 2, an 4 followe by 2 mg every 2 weeks) or plaebo + MTX. Results: At week 24, the Amerian College of Rheumatology riteria for 2% (ACR2) response rate was signifiantly greater with CZP + MTX than with plaebo (66.7% vs. 27.5%, p <.1). Differenes in ACR2 response rates for CZP vs. plaebo were signifiant from week 1 (p <.5) an remaine signifiant through week 24. The CZP group reporte signifiant improvement in physial funtion an isability ompare to the plaebo group (p <.1) at week 24, as assesse by Korean Health Assessment Questionnaire-Disability Inex (KHAQ-DI). Post ho analysis iniate that the proportion of patients who ha ACR7 responses, Disease Ativity Sore 28 (DAS28) low isease ativity, an DAS28 remission at week 24 was greater in CZP + MTX-treate patients who ahieve a erease in DAS (43.8%) at week 4 than in nonresponers. Among 18 (22.2%) an 14 patients (35.%) in CZP an plaebo groups who ha latent tuberulosis (TB), none evelope ative TB. Most averse events were mil or moerate. Conlusions: CZP treatment ombine with MTX in ative RA patients with moerate to severe isease ativity an an inaequate response to MTX resulte in rapi onset of effiay, whih is assoiate with better linial outome at week 24 an has an aeptable safety profile, espeially in an intermeiate TB-buren population. Keywors: Rheumatoi arthritis; Certolizumab; Methotrexate; Tumor nerosis fator inhibitor; Clinial trial Reeive : July 1, 216 Revise : August 2, 216 Aepte : Otober 26, 216 Corresponene to Soo-Kon Lee, M.D. Division of Rheumatology, Department of Internal Meiine, Severane Hospital, Yonsei University College of Meiine, 5-1 Yonsei-ro, Seoaemun-gu, Seoul 3722, Korea Tel: sookonlee@yuhs.a Copyright 218 The Korean Assoiation of Internal Meiine This is an Open Aess artile istribute uner the terms of the Creative Commons Attribution Non-Commerial Liense ( by-n/4./) whih permits unrestrite nonommerial use, istribution, an reproution in any meium, provie the original work is properly ite. pissn eissn

2 Kang YM, et al. Certolizumab in ative rheumatoi arthritis INTRODUCTION Rheumatoi arthritis (RA) is a hroni inflammatory isease assoiate with signifiant morbiity an mortality. The treatment of RA has shown remarkable avanement sine the evelopment of tumor nerosis fator (TNF) inhibitors ae an effetive armament on the syntheti isease-moifying anti-rheumati rugs (DMARDs), suh as methotrexate (MTX) an hyroxyhloroquine [1]. In aition to the new targete biologis, the refinement of TNF inhibiting agents has been unerway, whih inlues a fully human anti-tnf antiboy [2] an a PEGylate anti-tnf Fab antiboy [3], ertolizumab pegol (CZP). CZP has shown linial effiay in the treatment of RA with moerate to severe isease ativity either as a monotherapy or in ombination with MTX an other DMARDs [3-5]. The ombination of CZP an MTX was superior in the prevention of raiographi progression an in the improvement of physial funtion ompare with MTX monotherapy [3,4]. Improvements in linial outomes have been ahieve from the earliest visit after beginning of therapy (typially week 1) [3,4]. Previous stuies have shown that reuing linial isease ativity as muh as possible may result in the maximal reution of isability [6-8]. In aition, earlier response to treatment is preitive of the long-term outome [6]. Disease ativity at week 12 of treatment with TNF inhibitors has been relate to long-term linial an raiographi outomes [9]. Furthermore, rapi attainment of linial response at week 6 was assoiate with faster, more sustaine improvements in patienterive outomes an with a better hane of ahieving remission at week 52 ompare to response at week 12 [1]. This stuy was a phase 3, 24-week, ranomize, ouble-blin, plaebo-ontrolle trial in whih patients with moerate to severe RA an inaequate response to MTX oul be enrolle. The purpose of this stuy was to etermine the effiay an safety of CZP in RA patients from a single ethniity. In aition, this stuy analyze whether early response to treatment is assoiate with better 24-week linial outome. METHODS Stuy setting an esign This was a 24-week, phase 3, ouble-blin, ranomize, multienter, plaebo-ontrolle stuy onute from Deember 29 through August 211 at 15 enters in Korea (NCT993317). The Institutional Review Boar (KNUH_9-78) at eah partiipating enter approve the stuy protool. All patients provie written informe onsent, an the stuy was onute in aorane with the priniples of the Delaration of Helsinki as well as the relevant regulations an guielines [11]. Eligible patients were ranomize 2:1 to reeive either CZP 2 mg subutaneously every 2 weeks following a loaing ose of CZP 4 mg at week, 2 an 4, or plaebo (.9% saline), plus MTX. All patients ontinue MTX treatment at the same ose an route of aministration as at entry. Patients who faile to ahieve a response aoring to the Amerian College of Rheumatology riteria for 2% (ACR2) improvement at week 12 (an onfirme at the week 14 visit) were onsiere treatment failures. After the week 14 osing, these patients an patients who omplete the stuy at week 24 were offere the hoie of entering the open-label extension (OLE) stuy. If the patients elete to enter the OLE stuy, they were to omplete the assessments at week 24/withrawal assessments at week 16 of the present stuy. Partiipants Eligible patients were age 18 to 75 years with a iagnosis of RA, as efine by ACR 1987 riteria [12], for at least 6 months uration but not longer than 15 years. Patients ha to have ative isease at sreening an at baseline, efine by 9 tener joint ount base on 68 joints, 9 swollen joint ount base on 66 joints an either erythroyte seimentation rate (ESR) 3 mm/hr (Westergren) or C-reative protein (CRP) 15 mg/l [13]. MTX ha to be stable for at least 8 weeks prior to baseline visit with a minimum ose of 1 mg weekly. Exlusion riteria inlue any ative infetion (inluing urrently ative tuberulosis [TB]), positivity for hepatitis B virus surfae antigen (HBsAg), hepatitis C antiboy (HCV Ab), or human immunoefiieny virus (HIV) serum testing, unontrolle meial iseases, an rheumati iseases other than RA. Patients were also exlue if they ha reeive any biologial therapy

3 The Korean Journal of Internal Meiine Vol. 33, No. 6, November 218 for RA within 24 weeks prior to baseline (12 weeks for etanerept), ha a severe hypersensitivity or anaphylati reation with a biologial agent, or ha been resistant to previous anti-tnf therapy. Oral ortiosterois ha to be stable for at least 4 weeks an uring the trial with maximum ose of 1 mg/ay prenisolone equivalent. Doses of nonsteroial anti-inflammatory rugs were fixe for 2 weeks prior to baseline visit an uring the trial. Patients were sreene for TB aoring to the guielines using skin test with purifie protein erivatives (PPD) an hest X-ray. If the PPD skin test was positive (inuration 5 mm) or the patient ha ha lose ontat with patients with ative TB, but there was no linial or raiologi eviene of TB, patients oul be enrolle into the trial after aequate treatment for latent TB with isoniazi (up to 3 mg) initiate at least 1 month before ranomization. Effiay assessments Effiay assessments were arrie out at baseline an at week 1, 2, 4, 6, 8, 12, 14, 2, an 24/withrawal. The primary effiay enpoint was the ACR2 response at week 24. The seonary effiay variables were ACR2 response at week 12, ACR5/ACR7 response at week 12 an 24, an Korean Health Assessment Questionnaire- Disability Inex (KHAQ-DI) at week 24 [14,15]. Other effiay variables inlue ACR2/ACR5/ACR7 response rates at other time points, ACR ore omponents, healthrelate quality of life (HRQoL) as measure by the Short Form-36 (SF-36) health assessment tool [16], Disease Ativity Sore in 28 joints alulate by using ESR (DAS28 [ESR]), European League Against Rheumatism (EULAR) response riteria, an ESR [17]. Among the seonary effiay enpoints, patient-reporte outomes (PRO) inlue pain, patient s global assessment of isease ativity, physial funtion assessment using the KHAQ-DI, an HRQoL assesse using the SF-36 Health Survey. Safety evaluations Safety was assesse base on reporte averse events (AEs) whih were assesse at all visits an at 12-week follow-up after the last ose of investigational prout. Physial examination, laboratory tests, an hest raiography were monitore at preefine sheule. AEs that require hospitalization, resulte in eath, or ause isability were efine as serious AEs (SAEs). For immunologi analyses, auto-antiboies suh as anti-ouble strane DNA an antinulear antiboies were measure at baseline an week 24/withrawal visit an anti- CZP antiboies at baseline, week 1, 2, 4, 6, 8, 12, an 24. Statistial methos The sample size was etermine using preite rate of ACR2 response with 2:1 ranomization ratio for CZP an plaebo groups on the assumption of ACR2 response of 5% in the CZP group an 21% in the plaebo group. A sample size of 8 an 4 patients in CZP an plaebo groups respetively was estimate to be require to provie 9% power for a two-taile test with an alpha of.5. Effiay analyses were performe using the full analysis set (FAS) population (n = 121). For the responer analyses, patients who withrew for any reason or use resue meiation were onsiere as nonresponers from that time point onwars (nonresponer imputation). Sensitivity tests were arrie out on the ata impute using the last observation arrie forwar (LOCF) metho. All seonary an other enpoints, apart from responer analyses, were impute using LOCF. Where analysis of ovariane was arrie out on an effiay enpoint, baseline value was inlue in the moel as a ovariate an treatment group as a fator. Comparisons between the CZP + MTX an plaebo + MTX groups were performe using logisti regression with treatment group as a fator. Os ratios an 95% onfiene intervals are presente. p values of <.5 were onsiere to be statistially signifiant. Safety an tolerability analyses were performe in the safety population in all ranomize patients who reeive at least 1 ose of stuy rug. The number an perentages of patients reporting AEs were tabulate an analyze per the Meial Ditionary for Regulatory Ativities oing terms. RESULTS A total of 127 patients were ranomize into the stuy. Of these, 121 patients (FAS) reeive either CZP (n = 81) or plaebo (n = 4) plus MTX (Fig. 1). Substantially fewer

4 Kang YM, et al. Certolizumab in ative rheumatoi arthritis 176 Sreene for eligibility 127 Ranomize 4 Plaebo + MTX 81 CZP 2 mg + MTX a 18 (45.%) Withrawn ue to lak of effiay at week 16 2 (5.%) Withrawn overall 2 (5.%) Averse events 18 (45.%) Lak of effiay 2 (5%) Complete week (27.8%) Sreen failures 6 Exlue from the FAS 17 (21.%) Withrawn ue to lak of effiay at week (28.4%) Withrawn overall 4 (4.9%) Averse events 17 (21.%) Lak of effiay 2 (2.4%) Other reason 58 (71.6%) Complete week 24 Figure 1. Disposition of patients. FAS, full analysis set; MTX, methotrexate; CZP, ertolizumab pegol. a CZP 2 mg every 2 weeks is preee by CZP 4 mg at weeks, 2, an 4. patients were withrawn ue to lak of effiay or AEs relate to worsening of RA isease in the CZP + MTX group ompare to plaebo + MTX group (45% vs. 21%). At week 24, 58 patients (71.6%) in the CZP group omplete the stuy ompare with 2 patients (5.%) in the plaebo group. The mean age, perentage of female, boy mass inex, mean uration of RA, an rheumatoi fator positivity were similar between the groups (Table 1). At week 24, the ACR2 response rate (primary enpoint) was signifiantly greater in the CZP + MTX group ompare to the plaebo + MTX group (66.7% vs. 27.5%, p <.1) (Fig. 2A). ACR2 response rate at week 12 was also statistially signifiant for the CZP + MTX group ompare to the plaebo + MTX group (64.2% vs. 37.5%, respetively; p =.6). Meaningful ifferenes in ACR2 response rates between treatment groups began at week 1 (p =.13) an remaine through week 24 (p <.5 for eah omparison). The slope of inrease Table 1. Baseline harateristis of the FAS population Charateristi Plaebo + MTX (n = 4) CZP 2 mg + MTX (n = 81) Age, yr 5.8 ± ± 11.7 Female sex 35 (87.5) 72 (88.9) BMI, kg/m ± ± 3.1 Disease uration, yr 5.5 ± ± 4.2 Tener joint ount ± ± Swollen joint ount 17.7 ± ± 9.4 KHAQ Disability Inex 1.54 ± ±.68 Patient s assessment of arthritis pain, 1 VAS 68.1 ± ± 19.2 Patient s global assessment, 1 VAS ± ± 21. Physiian s global assessment, 1 VAS ± ± DAS28 using the ESR 7.46 ± ± 1.9 ESR, mm/hr 4. ( ) 5. (. 12.) CRP, mg/l ( ) ( ) RF positive 32 (8) 64 (79) Treatment status MTX ose, mg/wk 13.5 ± ± 2.5 Steroi use 35 (87.5) 7 (86.4) PPD skin test positivity 14 (35.) 18 (22.) Values are presente as mean ± SD, number (%), or meian (range). PPD skin test positivity was efine as inuration 5 mm in iameter. FAS, full analysis set; MTX, methotrexate; CZP, ertolizumab pegol; BMI, boy mass inex; KHAQ, Korean Health Assessment Questionnaire; VAS, visual analog sale; DAS28, Disease Ativity Sore 28; ESR, erythroyte seimentation rate; CRP, C-reative protein; RF, rheumatoi fator; PPD, purifie protein erivative

5 The Korean Journal of Internal Meiine Vol. 33, No. 6, November b 66.7 PBO + MTX (n = 4) CZP + MTX (n = 81) ACR2 PBO + MTX ACR2 CZP + MTX ACR5 PBO + MTX ACR5 CZP + MTX ACR7 PBO + MTX ACR7 CZP + MTX ACR2 A Patients (%) ACR2 a ACR5 a ACR7 B Patients (%) Weeks ACR5 ACR2 ACR5 ACR7 ACR7 DAS28 (ESR) hange from baseline C Weeks PBO + MTX (n = 4) CZP + MTX (n = 81) PBO + MTX (n = 4) CZP + MTX (n = 81) Weeks Figure 2. Clinial effiay of ertolizumab pegol (CZP) + methotrexate (MTX) or plaebo (PBO) + MTX in the treatment of patients with ative rheumatoi arthritis for 24 weeks. (A) Amerian College of Rheumatology (ACR) 2%, 5%, an 7% response riteria (ACR2, ACR5, an ACR7) response rates at week 24. (B) ACR2, ACR5, an ACR7 response rates over time, nonresponer imputation (NRI). (C) Mean hanges from baseline in the Disease Ativity Sore in 28 joints (DAS28; erythroyte seimentation rate [ESR]). (D) European League Against Rheumatism (EULAR) response riteria goo/moerate response rates over time, NRI. a p.5, b p.1 (vs. PBO + MTX, NRI), an p.5, p.1 (vs. PBO + MTX at eah time point, last observation arrie forwar). Goo/moerate response rate (%) D in ACR2 response rate between time points was most steep at week 1, followe by week 2 an week 4 whih were then followe by sustaine but slower improvements. The ACR5 an ACR7 responses at week 24 were statistially signifiant when omparing the CZP + MTX group with the plaebo + MTX group (43.2% vs. 2.%, p =.14 an 17.3% vs. 2.5%, p =.47, respetively) (Fig. 2A). One patient in the plaebo + MTX group an 14 patients in the CZP + MTX group ahieve an ACR7 response at week 24 (Fig. 2B). A treatment ifferene in improvement in DAS28 was observe by week 1 for patients reeiving CZP + MTX ompare to plaebo + MTX (mean hange from baseline:.7 vs..22, respetively; p <.1), an was maintaine until week 24 ( 2.3 vs..94, p <.1) (Fig. 2C). For the CZP + MTX group, by week 4, the mean hange of DAS28 from baseline approahe half of the improvement seen at week 24. EULAR goo/moerate response rates at weeks 4 an 24 for CZP + MTX group were 56.5% an 81.3%, respetively; versus 15.4% an 48.7%, respetively, for plaebo + MTX group (Fig. 2D). We next questione whether responses at as early as week 4 woul influene week 24 outomes. At week 4, both ACR2 an EULAR goo/moerate response rates were higher than 5% an the mean hange of DAS28 from baseline was approximate as almost half of the

6 Kang YM, et al. Certolizumab in ative rheumatoi arthritis improvement seen at week 24 for CZP + MTX group. Responers were then efine as patients ahieving a erease in DAS28 (ESR) of 1.2 from baseline. Post ho analysis reveale that the proportion of patients who ha ACR7 responses, DAS28 low isease ativity (LDA; efine as a DAS28 3.2), an DAS28 remission (efine as a DAS28 2.6) at week 24 was greater in the population of week 4 responers than in nonresponers (Fig. 3). CZP + MTX-treate patients who ahieve a DAS (43.8%) at week 4 ha similar emographis an isease harateristis at baseline (ata not shown) ompare with nonresponers. In aition to linial outomes, CZP + MTX provie measurable improvements in PROs, inluing pain, patient s global assessment for isease ativity, KHAQ-DI, an HRQoL over plaebo + MTX. At week 1, CZP + MTX group reporte signifiant improvement in pain, patient s global assessment, an KHAQ-DI. The mean hange from baseline in KHAQ-DI at week 24 was.54 with CZP + MTX ompare to.17 with plaebo + MTX (p <.1) (Fig. 4). Patients in the CZP + MTX group showe greater improvements from baseline in HRQoL as assesse by Physial Component Summary sore (PCS) an Mental Component Summary sore (MCS) of SF-36 ompare with those in the plaebo + MTX group. The ifferenes between treatment groups were small for the PCS ompare to the MCS, although all SF-36 omain sub-sores were numerially improve in patients treate with CZP + MTX ompare to plaebo + MTX. In a post ho analysis, DAS28 response at week 4 was assoiate with linially signifiant improvements in PROs suh as pain an patient s global assessment at week 24. Of the 127 patients in the safety set (patients who reeive at least one injetion of stuy rug), a total of 164 treatment emergent averse events (TEAEs) were reporte in 56 patients (65.9%) treate with CZP + MTX, whereas 6 TEAEs were reporte in 24 patients (57.1%) treate with plaebo + MTX (Table 2). The majority of AEs in both treatment groups were mil to moerate in nature. The most frequently reporte averse events were infetions, followe by gastrointestinal isorers an injetion site reations. Infetious AEs were reporte at similar rates in the CZP + MTX group (34.1%) an the plaebo + MTX group (28.6%). The most frequent infetious AEs were upper respiratory trat infetions an urinary trat infetions. AEs leaing to withrawal from the stuy were reporte in CZP + MTX patients (n = 4, 4.7%) an plaebo + MTX patients (n = 2, 4.8%). A total of 15 SAEs were experiene by eight patients (9.4%) in the CZP + MTX group ompare to none in the plaebo + MTX group. The most ommon SAEs were infetions ourring in six CZP-treate patients. At baseline, 18 (22.2%) an 14 patients (35.%) in the CZP + MTX an Perent (%) ACR LDA <1.2. Remission Figure 3. Proportion of Amerian College of Rheumatology (ACR) 7 responers, patients with low isease ativity (LDA), an patients in Disease Ativity Sore in 28 joints (DAS28) remission at week 24 in patients who ahieve a 1.2-point reution ompare with patients who ahieve a < 1.2-reution in DAS28 at week 4. KHAQ-DI hange from baseline Weeks a PBO + MTX CZP + MTX a Figure 4. Mean hange from baseline in Korean Health Assessment Questionnaire-Disability Inex (KHAQ-DI) until week 24. PBO, plaebo; MTX, methotrexate; CZP, ertolizumab pegol. a p.5, b p.1, an p.1 vs. PBO + MTX at eah time point, last observation arrie forwar. b a

7 The Korean Journal of Internal Meiine Vol. 33, No. 6, November 218 Table 2. Summary of AEs AE Plaebo + MTX (n = 42) CZP + MTX (n = 85) No. of patient (%) a Total event No. of patient (%) a Total event Total AEs 24 (57.1) 6 56 (65.9) 164 Infetious AEs 12 (28.6) (34.1) 46 Upper respiratory trat infetion 5 (11.9) 5 12 (14.1) 12 Urinary trat infetions 1 (2.4) 1 2 (2.4) 2 Tuberulosis 2 (2.4) 2 Neoplasms 2 (2.4) 2 Serious AEs 8 (9.4) 15 Serious infetions 6 (7.1) 8 Nervous system isorers 2 (2.4) 4 AEs leaing to withrawal 2 (4.8) 6 4 (4.7) 8 AEs leaing to eath AE, averse event; MTX, methotrexate; CZP, ertolizumab pegol. a Patients who experiene more than one AE in a ategory are liste one. plaebo + MTX groups, respetively, ha PPD inurations 5 mm in iameter (Table 1). All of these patients exept for one reeive prophylati treatment for TB. One subjet in the plaebo + MTX group i not reeive TB prophylaxis espite PPD positivity an was reporte as a protool eviation. This subjet in t experiene TB uring the stuy. Two patients evelope TB after 147 an 167 ays of exposure to CZP. Both patients were PPD negative at baseline. There were no ases of eath, emyelinating iseases, malignany, or lupus-like synrome. The iniene of onversion of antinulear antiboy from negative at baseline to positive at week 24 was higher in the CZP + MTX group (11.1%) than the plaebo + MTX group (7.1%). One patient (2.4%) in the plaebo group onverte anti-ouble strane DNA (anti-sdna) antiboy from negative at baseline to positive at week 24. Anti-CZP antiboies were etete in 1.3% an 3.8% of CZP + MTX group at week 12 an week 24, respetively. DISCUSSION This 24-week ranomize ontrolle trial emonstrate that aition of CZP (4 mg at week, 2, an 4, followe by 2 mg every other week) to MTX in ative RA patients who ha a previous inaequate response to MTX alone rapily improve isease ativity. This stuy was performe in patients of single ethniity with an intermeiate TB buren, an emonstrate a similar effiay of CZP treatment ompare with that of previous stuies on a multi-ethniity bakgroun [3,4], an omparable risks for AEs inluing TB infetion. The primary enpoint, ACR2 response rate at week 24, was 66.7% in the CZP + MTX group, whih was slightly higher ompare to 58.5% an 57.3% in Rheumatoi Arthritis Prevention of strutural Damage 1 (RAPD1) [3] an RAPID2 [4] trials, respetively, but the response rate of plaebo group was also higher in this stuy. The os of being an ACR2 responer at week 24 was 5.3 times greater for patients in the CZP 2 mg plus MTX group ompare to the plaebo + MTX group (95% onfiene interval, 2.3 to 12.1; p <.1). The effiay of CZP + MTX was also emonstrate for all seonary an other enpoints, showing rapi response as early as week 1 an onsistent improvement throughout week 24 ompare to plaebo + MTX. A rapi hange in ACR2 response rate, DAS28 reution an KHAQ-DI improvement ontinue until week 4, whih was followe by slower but ontinuous improvements at subsequent visits. At week 24, a higher perentage of patients in the CZP + MTX group ahieve ACR5 an ACR7 response ompare to those in the plaebo + MTX group. CZP + MTX treate patients reporte signifiant improvement in physial funtion an isability ompare to plaebo + MTX patients (p <.1), as assesse by the KHAQ-DI

8 Kang YM, et al. Certolizumab in ative rheumatoi arthritis Furthermore, CZP-treate patients showe an improvement from baseline in health-relate quality of life, as assesse by SF-36 PCS an MCS. In a post ho analysis, patients that ha erease DAS from baseline response at week 4 to CZP + MTX showe a better response in linial outomes an PROs at week 24, revealing that early linial response to CZP treatment is assoiate with goo linial responses in terms of ACR7, LDA, an DAS28 remission after longer term treatment at week 24. Although it was not the fous of the present trial, it was of interest that the earlier responers at week 4 ha a better linial outome measure. Previous stuies showe that the level of isease ativity at 3 months was relate to the inrease possibility of LDA or remission after 1 year of treatment with TNF inhibitors [6]. Furthermore, patients with an earlier linial response to CZP + MTX at week 6 were more likely to have a better long-term linial response at week 52 [1]. The response to anti-tnf treatment at week 6 may preit rug isontinuation at 3 months [18]. These results inluing the present stuy impliate that the faster response to TNF blokae preits improve long-term linial outome, whih may help reue unneessary rug exposure by earlier etermination of alternative therapy [1]. CZP + MTX in the present trial ha a omparable safety profile to other anti-tnfs, with a low iniene of isontinuations ue to AEs [3,4,19-21]. The perentage of CZP patients reporting infetious AEs was similar to those reporte for other TNF inhibitors in a population of the same ethniity [22] an in heterogeneous populations of multi-ethniity [3-5]. There were no eaths or malignany among patients who partiipate in this stuy. The iniene of serious infetions, inluing TB, in the CZP + MTX group was onsistent with those reporte with anti-tnf treatments [23,24]. In the present stuy whih was performe in an intermeiate TB-buren population (92/1, general population) [25], TB ourre in two patients with CZP treatment. Although patients who were onsiere to have a risk of TB were treate with a prophylati regimen base on the urrent linial proeures using guielines for latent TB treatment uring TNF antagonist use [26,27] TB may still our in patients with negative PPD skin tests, representing new infetions rather than reativations [28]. The omparable iniene of TB in this stuy with the trials of TNF inhibitors performe in mixe TB-buren populations iniates the safety of CZP therapy in patients living in ountries with an intermeiate prevalene of TB, if appropriate prophylati measures are applie [4,19-21]. Thus, CZP + MTX has an aeptable safety profile for the treatment of patients with RA whih was in line with other reports of CZP [3,29] an with reports of other anti-tnfs in the same population [22]. Limitations of this stuy inlue the short uration of 24 weeks, small size of stuy population an lak of raiographi outome measures. Further long-term ata by the OLE to this stuy an aitional registry programs may assist in ientifiation of better preitors of long-term linial outome. In onlusion, ombine treatment with CZP in patients with ative RA an an inaequate response to MTX resulte in rapi onset of effiay whih is assoiate with better linial outome at week 24 an has an aeptable safety profile, even in an intermeiate TB-buren population with aequate TB prophylaxis management. Together with establishe effiay, these results augment the available eviene that CZP treatment is safe an effetive in the treatment of RA patients with moerate to severe isease ativity. KEY MESSAGE 1. Certolizumab pegol treatment ombine with methotrexate (MTX) in patients with ative rheumatoi arthritis an an inaequate response to MTX resulte in rapi onset of effiay. 2. Rapi onset of effiay was assoiate with better linial outome at week 24, even in an intermeiate tuberulosis (TB)-buren population with aequate TB prophylaxis management. Conflit of interest We orially appreiate the support of Marion Boehnlein from UCB. This linial trial was fully fune by Korea Otsuka Pharmaeutial Co. Lt., the sponsor of this stuy

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